SUMO Modulation of Protein Aggregation and Degradation
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AIMS Molecular Science, 2(4): 382-410 DOI: 10.3934/molsci.2015.4.382 Received date 14 July 2015, Accepted date 30 August 2015, Published date 6 September 2015 http://www.aimspress.com/ Review SUMO modulation of protein aggregation and degradation Marco Feligioni1, *, Serena Marcelli1,2, Erin Knock3, Urooba Nadeem4 Ottavio Arancio4 and Paul E. Fraser3,5 1 Laboratory of Synaptic Plasticity, EBRI Rita Levi-Montalcini Foundation, Via del Fosso di Fiorano 64/65, Rome 00143, Italy 2 Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, 00185, Italy 3 Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada 4 Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, 630 W 168th St., New York, NY 10032, USA 5 Department of Medical Biophysics, University of Toronto, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada * Correspondence: Email: [email protected]; Tel: 39 06 501703112. Abstract: Small ubiquitin-like modifier (SUMO) conjugation and binding to target proteins regulate a wide variety of cellular pathways. The functional aspects of SUMOylation include changes in protein-protein interactions, intracellular trafficking as well as protein aggregation and degradation. SUMO has also been linked to specialized cellular pathways such as neuronal development and synaptic transmission. In addition, SUMOylation is associated with neurological diseases associated with abnormal protein accumulations. SUMOylation of the amyloid and tau proteins involved in Alzheimer’s disease and other tauopathies may contribute to changes in protein solubility and proteolytic processing. Similar events have been reported for α-synuclein aggregates found in Parkinson’s disease, polyglutamine disorders such as Huntington’s disease as well as protein aggregates found in amyotrophic lateral sclerosis (ALS). This review provides a detailed overview of the impact SUMOylation has on the etiology and pathology of these related neurological diseases. Keywords: SUMO; neurodegeneration; Alzheimer’s disease; Parkinson’s disease; Amyotrophic lateral sclerosis; Huntington’s disease; tau; amyloid; synuclein; superoxide dismutase; TAR DNA-binding protein-43 383 1. The SUMOylation pathway SUMOylation is a process by which polypeptides called small ubiquitin-related modifiers (SUMOs), are covalently linked to lysine residues of cellular target proteins. Mammalian cells express three major paralogues, SUMO1, SUMO2 and SUMO3. The latter two SUMO subtypes are similar to each other in structure, and are commonly referred to as SUMO2/3. The process of SUMOylation is similar to ubiquitination and involves activating (SUMO-E1), conjugating (SUMO-E2) and SUMO-E3 enzymes (Figure 1). The SUMO proteins are initially cleaved at their C-terminus by Sentrin-specific proteases (SENP) to expose a diglycine (GG) motif. The mature SUMO is activated in an ATP-dependent pathway to a complex of SUMO activating enzyme E1 (SAE1) and SAE2 where SUMO is covalently attached via a thioester bond to a cysteine residue in SAE2. The SUMO moiety is subsequently transferred to an active cysteine site within the SUMO conjugating enzyme, Ubc9. The latter enzyme transfers SUMO to a lysine residue in the target protein via a non-covalent complex with a SUMO-E3 ligase of which there are multiple species. The general consensus sequence for SUMO conjugation is ѱKxE/D where ѱ is bulky hydrophobic residue and x can be any amino acid followed by an acidic residue. The SUMOylation cycle is then completed by the removal of SUMO from its target protein by one of the SENPs [1]. Figure 1. Protein SUMOylation pathway. The cycle begins with the cleavage of SUMO proteins into mature forms by the specific isopeptidases SENPs. The removal of the C-terminal end amino acids of SUMO leads to the activation of the protein by ATP that allows the binding with E1 heterodimer. SUMO is then transferred to the specific E2 enzyme Ubc9 that guides SUMO onto the target protein by recognizing the lysine residue within the SUMOylation motif. E3 enzymes enter into the SUMO cycle to increase the AIMS Molecular Science Volume 2, Issue 4, 382-410. 384 efficiency of the ligation reaction. SENPs removes SUMO from the target protein by cleaving the isopeptidic bond and SUMO proteins are therefore again able to enter in a second SUMOylation cycle. The effects of protein SUMOylation vary depending on the target and include altered subcellular localization, activity and stability. SUMOylation may have the effect of revealing or blocking sites for other post-translational modifications such as ubiquitination or phosphorylation. SUMOylation of target proteins can also promote novel protein interactions by non-covalent binding of proteins with SUMO interacting motifs (SIMs). Many proteins with SIMs recognize poly-SUMO chains, which are formed by SUMO2/3 rather than mono-SUMO conjugates formed by SUMO1. Interestingly, several ubiquitin E3 ligases were found to have SIMs suggesting that in some cases protein SUMOylation may help target a protein for degradation (reviewed in [2,3]). 2. SUMOylation and neurodegenerative diseases SUMO modification of several proteins has been linked to Alzheimer’s (AD), tauopathies, and Parkinson’s disease (PD) as well as ALS and Huntington’s disease (HD). The functional impact of SUMO can involve different pathways related to the production, aggregation and/or clearance of misfolded proteins that are found in these neurodegenerative disorders. SUMOylation has been shown to be involved in the amyloid pathology in AD, potentially by altering the processing and/or trafficking of the amyloid precursor protein, as well as at its downstream level. In addition, conjugation of SUMO1 to the microtubule associated tau protein leads to changes in phosphorylation and subsequent aggregations that may contribute to neurofibrillary tangle (NFT) formation in various tauopathies. Similar effects of SUMOylation have been reported for the huntingtin (Htt) protein and related polyglutamine repeat diseases as well as superoxide dismutase (SOD) and the TAR DNA-binding protein-43 (TDP-43) associated with ALS, although the effect of SUMOylation on TDP-43 is very poorly known. SUMOylation seems to have instead a disaggregation effect on α-synuclein, that is linked to PD, since it abolishes its fibril formation in vitro. This review discusses in detail the contributions of SUMOylation to the etiology and pathology of these related neurological diseases. 3. SUMOylation and AD and other tauopathies AD is a debilitating, progressive neurodegenerative disease, recognized as the most common cause of chronic dementia among the aging population. A progressive impairment in cognitive function due to subtle changes in cellular communication characterizes the onset of the disease, whose pathological progression ends up with a severe synaptic dysfunction leading to significant cognitive deficits in recognition, language and skilled movements [4,5]. Since no effective treatment for AD currently exists, efforts have focused on understanding the molecular mechanisms of the AD-related synaptotoxicity and neuronal loss. The hallmarks recognized for AD are senile plaques, composed primarily of amyloid-β (Aβ) peptides, and NFTs that are the result of accumulations of hyperphosphorylated tau [6,7]. These plaque and tangle pathological features are accompanied by neuroinflammation related to glial cell activation which is considered to be a fundamental contributor to AD pathogenesis [8,9]. AIMS Molecular Science Volume 2, Issue 4, 382-410. 385 Several lines of evidence support the dysregulation of SUMOylation in AD. SUMO2 levels, particularly the high molecular weight region (> 75 kD) (but not SUMO1 or ubiquitin levels), are decreased in the hippocampal formation of AD or other Tauopathies patients [10]. Additionally, an association between a single nucleotide polymorphism (SNP) in genes encoding SUMO enzymes, including Ubc9 and a homolog of SAE2 [11–13] has been found in patients with either sporadic late-onset AD or mild cognitive impairment (MCI) [11]. 3.1. SUMOylation and amyloid precursor protein Several studies have found a potential relationship between APP and SUMOylation. This is noteworthy given that aggregation and accumulation of misfolded proteins is a primary causative factor in AD, particularly as it relates to the Aβ protein production derived from proteolytic process of amyloid precursor protein (APP) [14]. Global changes in SUMO1 and SUMO2/3 conjugation levels are present in the Tg2576 transgenic mouse models of AD [15,16]. Interestingly, APP levels are dramatically increased in the hippocampus, cortex and cerebellum of these mice while elevations of ubiquitinated proteins is mainly observed in the hippocampus [16]. A recent study conducted an age-related analysis of the expression levels of SUMOylated proteins in the Tg2576 mouse [15]. At early stages of the pathology (~ 3 months), significant differences in the SUMOylation patterns were detected, with increases of SUMO1 conjugation at 3 and 6 months of age, but not at 17 months, accompanied by similar patterns of increases for Ubc9 and SENP1. The same study revealed a decrease for SUMO2 conjugation only at later ages (17 months). Consistent with these studies, high molecular weight SUMO2/3 conjugates (> 75 kD) were found to be reduced after 7 months (just prior to the onset of widespread amyloid plaque deposition)